BR112016016841B1 - TOPIC ADMINISTRATION FORMULATION - Google Patents

Abstract

TOPICAL ADMINISTRATION FORMULATION The present invention is a pour-on antiparasitic formulation having superior water resistance properties. The pour-on formulation uses one or more polymers (water insoluble with or without water soluble) in the range of about 5 to about 40% w/w, one or more solvents in the range of about 50 to about 94 % w/w, with or without additive (e.g. isopropanol or ethanol) in the range of about 5 to about 30% w/w, and optionally a plasticizer in the range of about 0.5 to about 25 % w/w. The characteristic of the antiparasitic pour-on formulation and limited propagation when applied to animals (cattle, sheep, dogs and the like). The pour-on antiparasitic formulation also partially evaporates, leaving a water-resistant polymer matrix that diffuses at least one active ingredient into the animal's skin.

Description

CROSS REFERENCE TO RELATED ORDERS

[0001] This application claims priority to US Provisional Patent Application No. US 61/929,371, filed January 20, 2014.

FIELD OF INVENTION

[0002] The present invention generally relates to topical administration systems and their manufacture. More specifically, the present invention relates to topical antiparasitic delivery systems for animals.

BACKGROUND OF THE INVENTION

[0003] Animals such as mammals are often susceptible to parasite infestations. These parasites can be ectoparasites such as insects and endoparasites such as filariae and worms. Domesticated animals such as cats and dogs are often infested with one or more of the following ectoparasites: - fleas (Ctenocephalides felis, Ctenocephalides sp. and the like), - Ticks (Rhipicephalus SP, Ixodes sp, Dermacentor sp, Amblyomma sp. and the like), - Mites (Demodex sp, Sarcoptes sp, Otodectes sp. and the like), - Lice (Trichodectes sp, Cheyletielfa sp., Linognathus sp., and the like), and - Flies (Hematobia sp, Musca sp., Stomoxys sp., Dermatobia sp., Cochliomyia sp. and mosquitoes (family Culicidae) and the like).

[0004] Fleas are a particular problem, not only because they negatively affect the health of the animal or human being, but also cause a great deal of psychological stress. In addition, fleas are also vectors of pathogens in animals, such as the dog tapeworm (Dipylidium caniem um) and can also transmit pathogens to humans.

[0005] Likewise, ticks are also harmful to the physical and psychological health of the animal or human being. However, the most serious problem associated with ticks is that they are the vector for pathogens, which can cause disease in humans and animals. Major diseases that are caused by ticks include borreliosis (Lyme disease caused by Borrelia burgdorferi), babesiosis (or piroplasmosis caused by Babesia sp.), and Rickettsiosis (also known as Rocky Mountain spotted fever). Ticks also release toxins that cause inflammation or paralysis in the host. Occasionally, these toxins are fatal to the host, as in the case of the Australian paralysis tick, Ixodes holocyclus.

[0006] In addition, mites and lice are particularly difficult to combat since there are few active substances that act on these parasites and they require frequent treatment.

[0007] Likewise, farm animals are also susceptible to parasite infestations. For example, cattle are affected by a large number of parasites (eg arthropod pests such as fleas, lice and ticks and mites). A parasite that is very prevalent among farm animals is the tick of the genus Boophilus, especially those of the micropJus (tick), decoloratus and anulatus species. Ticks such as Boophilus microplus are particularly difficult to control because they live in the pasture where farm animals graze. Other important parasites of cattle and sheep are listed below: (a) myiasis, such as Dermatobia hominis (known as Berne in Brazil), Hypoderma, and Cochlyomia hominivorax (green bottle); Sheep myiasis such as Lucilia sericata, Lucilia cuprina (known as blowfly attack in Australia, New Zealand and South Africa). These are flies whose larvae constitute the animal parasite; (b) fly itself, ie, those whose adult constitutes the parasite, such as Haematobia irritans (ie, horn fly); (c) lice, such as Linognathus vitui, etc.; and (d) mites, such as Sarcoptes scabiei and Psoroptes ovis.

[0008] The above list is not exhaustive and other ectoparasites are well known in the prior art to be harmful to animals.

[0009] Protection of animals against parasites is essential to ensure a healthy and safe environment for animals and their owners. Topical pour-on and spot-on formulations are widely used to provide treatment against a variety of external and internal parasites such as ticks, fleas, flies, mites, worms, etc. These formulations are solutions that are applied to the back of an animal and allowed to spread or penetrate. To be effective, these formulations need to retain an active in the upper layers of the skin or direct an active to the skin for systemic absorption, and to be able to withstand environmental stress (eg, rain), to prevent drug removal. Depending on the intended use, topical formulations typically consist of a solvent with or without a penetration enhancer (for systemically administered drugs) or a solvent or co-solvents with added spreading agent, and various performance additives to deliver overcoats. of the skin.

[00010] This is a traditional approach to formulating a pour-on or spot-on topical solution. Topical pour-ons currently marketed to farm animals for protection against external parasites do not have good water resistance and need to be reapplied frequently.

[00011] For example, commercial products for the control of horn fly in cows provide limited protection lasting several days to two weeks and require reapplication after rain throughout the fly season. This creates unnecessary stress for the animals, resulting in lost productivity and significant additional work efforts for the farmers.

[00012] Current commercially available topical solutions for controlling the horn fly population in cows provide limited duration of protection lasting from several days to about two weeks. Current treatments require more frequent re-application due to a wash-off after exposure to environmental conditions such as rain.

[00013] Extension of effectiveness of one month or more will provide continuous protection against horn fly with less frequent applications. Fewer applications will be less stressful for the animals and less time and less labor consuming for the farmers.

[00014] There are several issues that contribute to the short duration of the active ingredient(s) in current non-systemic pour-on formulations. First, the conventional solvent system (organic solvents) applied topically is expected to spread the active ingredient and retain it on the skin for the duration of the desired treatment period. Second, a full dose intended to last for the duration of the treatment period is applied at the same time. Third, conventional solvent systems are not well formulated to withstand some time challenges. The active ingredient is completely exposed to environmental conditions. The solvent carrying the active ingredient is washed away during rain, making it ineffective. Fourth, the solvent system may not remain in the animal during the treatment process, resulting in an ineffective treatment.

[00015] Compounds that exhibit a degree of activity against a wide range of ectoparasites including arthropods and insects are known in the prior art. One such class of compounds is the arylpyrazoles which are mentioned, for example, in US Patent Nos. 5,122,530; 5,246,255; 5,576,429; 5,885,607; 6,010,710; 6,083,519; 6,096,329; 6,685,954; EP 0,234,119 and EP 0,295,117 (US Patent Nos. 5,232,940; 5,547,974; 5,608,077; 5,714,191; 5,916,618 and 6,372,774); EP 0 352 944 (U.S. Patent No. 4,963,575); EP 0780378 (US Patent Nos. 5,817,688; 5,922,885; 5,994,386; 6,124,339; 6,180,798 and 6,395,906); EP 0846686 (US Patent No. 6,069,157); WO 98/28278, WO 08/05489, US 7,759,381 and US 8,445,519. All of the aforementioned patents and patent publications are incorporated herein by reference.

[00016] Arylpyrazoles are known to have excellent activity against insects such as fleas and ticks. Fipronil is a specific type of 1-N-arylpyrazole that is particularly effective against fleas and ticks and is the frontline active ingredient in Frontline® Plus®. Another arylpyrazole, 1-(2-chloro-6-fluoro-4-trifluoromethylphenyl)-4-methylsulfinyl-dichlorofluoro-5-methylpyrazole-3-carbonitrile has similar structure and properties to fipronil.

[00017] Other classes of compounds are also known in the prior art to be effective parasiticides.

[00018] Examples include macrocyclic lactones (e.g. avermectins and their derivatives ivermectin, eprinomectin, selamectin, doramectin and abamectin), benzimidazoles (e.g. triclabendazole), levamisole, closantel and growth inhibitors such as S-methoprene.

[00019] There is a need for a formulation that can be applied as a pour-on or spot-on formulation, but offers greater water resistance and extended duration of effectiveness. This will lessen stress for the animals and avoid the labor and costs associated with multiple pour-on applications. It will avoid more work and costs associated with fixing and retrieving ear tags.

SUMMARY OF THE INVENTION

[00020] The topical solution of the invention includes at least one active ingredient and a volatile solvent system that contains at least one dissolved polymer. The solvent system is not designed to maximize diffusion but instead has some spread and evaporates for shortly after dosing, leaving a water resistant film of the polymer on the skin and hair. This may consist of a contiguous film or a conglomerate of polymer particles that adhere to an animal's hair and skin. Upon evaporation of the volatile solvent(s), the active(s) encapsulated in the polymer will diffuse out at a specified rate and be transported by lipids from the skin of an animal. The active(s) need to be able to dissolve not only in the volatile solvent system, but also in the polymer. The rate of diffusion can be influenced by solvent selection, their proportions, polymer selection, the addition of a plasticizer(s) and their chemical composition, or by the skin lipids naturally occurring in the skin. The selection of excipients will also impact such formulation properties as water resistance, flow during dosing and duration of efficacy.

[00021] The invention provides an increase in the duration of effectiveness of a topical formulation, through the use of a polymer dissolved in the formulation. As the formulation dries onto surfaces (either hair or skin), the active ingredient is trapped in the resulting polymer matrix. The rate of release of the active ingredient can be controlled by incorporating and adjusting the amount of a "plasticizer" (i.e., a solvent that is fluid, in which the polymer is solidified). The resulting polymer matrix will then perform similarly to the transdermal patch or traditional ear tag.

[00022] In one aspect, the invention is a formulation for topical administration with one or more solvents to include aliphatic ketones, esters and saturated alcohols. The invention further includes a water-insoluble polymer alone or in combination with a water-soluble polymer, and, optionally, a plasticizer.

[00023] Examples of solvents include, but are not limited to, methyl isobutyl ketone, butyl acetate, ethyl lactate, isopropyl alcohol or ethanol. Examples of water-insoluble polymers include, but are not limited to, vinyl acetate, polyisobutene, methacrylates, polyurethanes, styrenes, and polyolefin elastomers. Non-limiting examples of water-soluble polymers include povidone, polyvinyl alcohol, polyacrylic acid and cellulose acetate. The optional plasticizer can be, for example, an aliphatic ester such as acetyl tributyl citrate. Other esters can function as plasticizers, for example triethyl citrate, tributyl citrate, acetyl triethyl citrate, cetearyl palmitate and lanolin. In addition, polymers (eg, polybutene), oils (eg, castor oil), and propylene glycol and propylene glycol esters can function as plasticizers. Oily actives such as pyrethroids (eg permethrin) and growth regulators (eg methoprene,(s)) can also act as plasticizers.

[00024] In another aspect, the invention is a method of making a topically administrable formulation using the optional solvents, polymers and plasticizers described herein.

[00025] In yet another aspect, the invention is a use of a topically administered formulation for the manufacture of a medicament for the therapeutic treatment and/or prophylactic treatment of an animal against an ectoparasite and/or an endoparasite.

DETAILED DESCRIPTION OF THE INVENTION

[00026] In one aspect, the invention is a formulation for topical administration with one or more solvents to include aliphatic ketones, esters and saturated alcohols. The invention further includes a water-insoluble polymer alone or in combination with a water-soluble polymer, and, optionally, a plasticizer.

[00027] Examples of solvents include, but are not limited to, methyl isobutyl ketone, butyl acetate, ethyl lactate, isopropyl alcohol or ethanol. A non-limiting example of a water-insoluble polymer is vinyl acetate. Non-limiting examples of water-soluble polymers include povidone, polyvinyl alcohol or cellulose acetate. The optional plasticizer may be an aliphatic ester, such as acetyl tributyl citrate.

[00028] Veterinarily active ingredients, which include, but are not limited to, anthelmintics, acaricides, antiparasitics, insecticides and insect repellents, may also be added to the compositions of the invention. Antiparasitic agents may include both ectoparasiticide and endoparasiticidal agents. These agents are well known in the art (see, for example, Plumb' Veterinary Drug Handbook, 5th edition, ed. Donald C. Plumb, Blackwell Publishing, (2005) or The Merck Veterinary Manual, 9th Edition, (January 2005) and include, but are not limited to, acarbose, acepromazine maleate, acetaminophen, acetazolamide, sodium acetazolamide, acetic acid, acetohydroxamic acid, acetylcysteine, acitretin, acyclovir, albendazole, albuterol sulfate, alfentanil HCl, allopurinol, alprazolam, altrenogest, amantadine HCl, sulfate amikacin, aminocaproic acid, aminopentamide hydrogen sulfate, aminophylline/theophylline, amiodarone HCl, amitraz, amitriptyline HCl, amlodipine besylate, ammonium chloride, ammonium molybdenate, amoxicillin, amoxicillin, potassium clavulanate, amphotericin B deoxycholate, amphotericin B based on lipid, ampicillin, amprolium HCl, antacids (oral), antivenin, apomorphion HCl, apramycin sulfate, ascorbic acid, asparaginase, aspirin, atenolol, atipamezole HCl, atracurium besylate, atropine sulfate, aurnofin, aurothioglucose, azaperone, azathioprine, azithromycin, baclofen, barbituates, benazepril HCl, betamethasone, bethanechol chloride, bisacodyl, bismuth subsalicylate, bleomycin sulfate, boldenone undecylenate, bromides, bromocriptine mesylate, budenoside, buprenorphine HCl, buspirone HCl, busulfan, butorphanol tartrate, cabergoline, calcitonin salmon, calcitrol, calcium salts, captopril, carbenicillin indanyl sodium, carbimazole, carboplatin, carnitine, carprofen, carvedilol, cefadroxil, cefazolin sodium, cefixime, cefoperazone sodium, cefotaxime sodium, cefotetan disodium, cefoxitin sodium, cefpodoxime proxetil, ceftazidime, ceftiofur sodium, ceftiofur HCI, ceftiaxone sodium, cephalexin, cephalosporins, cefapirin, charcoal (activated), chlorambucil, chloramphenicol, chlordiazepoxide, chlordiazepoxide +/- male chlorophenzimide, clidinium brodinamine , chlorpromazine HCl, chlorpropamide, chlortetracycline, gonadotr chorionic opine (HCG), chromium, cimetidine, ciprofloxacin, cisapride, cisplatin, citrate salts, clarithromycin, clemastine fumarate, clenbuterol HCl, clindamycin, clofazimine, clomipramine HCl, claonazepam, clonidine, cloprostenol sodium, dipotassium chlorazepate, clorsulon, cloxacillin, phosphate codeine, colchicine, corticotropin (ACTH), cosyntropin, cyclophosphamide, cyclosporine, cyproheptadine HCl, cyproheptadine HCl, cytarabine, dacarbazine, dactinomycin/actinomycin D, dalteparin sodium, danazol, dantrolene sodium, dapsone, decoquinate, deferoxamine mesylate, deracoxib, deslorelin acetate, acetate desmopressin, desoxycorticosterone pivalate, detomidine HCl, dexamethasone, dexpanthenol, dexraazoxane, dextran, diazepam, diazoxide (oral), dichlorphenamide, dichlorvos, diclofenate sodium, dicloxacillin, diethylcarbamazine citrate, diethylstilbestrol (DES), difloxacin HCl, digoxin, dihydrotacysterol (DHT) ), diltiazem HCl, dimenhydrinate, dimercaprol/BAL, dimethyl sulfoxide, dinoprost tromethamine, diphenylhydramine HCl, disopyramide phosphate, dobutamine HCl, docusate, dolasetron mesylate, domperidone, dopamine HCl, doramectin, doxapram HCl, doxepin HCl, doxorubicin HCl, doxycycline, disodium calcium edetate, calcium EDTA, edrophonium chloride, enalapril, enoxaparin sodium, enrofloxacin, ededrine sulfate, epinephrine, epoetin/erythropoietin, eprinomectin, epsiprantel, erythromycin, esmolol HCl, estradiol cypionate, ethacrynic acid/sodium ethacrynate, ethanol (alcohol), etidronate sodium, etodolac, etomidate, euthanasia agents w/pentobarbital, famotidine , fatty acids (essential/omega), felbamate, fenbendazole, fentanyl, ferrous sulfate, filgrastim, finasteride, fipronil, florfenicol, fluconazole, flucytosine, hydrocortisone acetate, flumazenil, flumethasone, f1unixin meglumine, fluorouracil (5-FU), fluoxetine, fluticasone propionate, f1uvoxamine maleate, fomepizole (4-MP), furazolidone, furosemide, gabapentin, gemcitabine HCl, gentamicin sulfate, glimepirid a, glipizide, glucagon, glucocorticoid agents, glucosamine/chondroitin sulfate, glutamine, glyburide, glycerin (oral), glycopyrrolate, gonadorelin, grisseofulvin, guaifenesin, halothane, hemoglobin glutamer-200 (oxyglobln®), heparin, hetastarch, sodium hyaluronate, hydrazaline HCl, hydrochlorothiazide, hydrocodone bitartrate, hydrocortisone, hydromorphone, hydroxyurea, hydroxyzine, ifosfamide, imidacloprid, imidocarb dipropinate, sodium impenemcillasttin, imipramine, inamrinone lactate, insulin, interferon alfa-2a (recombinant human), iodide (sodium/potassium), ipecac ( syrup), sodium ipodate, ferric dextran, isoflurane, isoproterenol HCl, isotretinoin, isoxsuprine HCl, itraconazole, ivermectin, kaolin/pectin, ketamine HCl, ketoconazole, ketoprofen, ketorolac tromethamine, lactulose, leuprolide, levamisole, levetiracetam, levothyroxine sodium, lidocaine HCl , lincomycin HCl, liothyronine sodium, lisinoprll, lomustine (CCNU), lufenuron, lysine, magnesium, mannitol, marbofloxacin, m echlorethamine HCl, meclizine HCl, meclofenamic acid, medetomidine HCl, medium chain triglycerides, medroxyprogesterone acetate, megestrol acetate, melarsomine, melatonin, meloxican, meldalan, meperidine HCl, mercaptopurine, meropenem, metformin HCl, methadone HCl, metazolamide, methenamine mandelate /hippurate, methimazole, methionine, methocarbamol, methohexital sodium, methotrexate, methoxyflurane, methylene blue, methylphenidate, methylprednisolone, metoclopramide HCl, metoprolol, metronidaxol, mexiletine HCl, mibolerlone, midazolam HCl, milbemycin oxime, mineral oil, minocycline HCl, misoprostol, mitotane, mitoxantrone HCl, morantel tartrate, morphine sulfate, moxidectin, naloxone HCl, mandrolone decanoate, naproxen, narcotic analgesic (opiate) agonists, neomycin sulfate, neostigmine, niacinamide, nitazoxanide, nitenpyram, nitrofurantoin, nitroglycerin, sodium nitroprusside, nizatidine , novobiocin sodium, nystatin, octreotide acetate, olsalazine sodium, om eprozole, ondansetron, opiate antidiarrhea, orbifJoxacin, oxacillin sodium, oxazepam, oxfendazole, oxybutynin chloride, oxymorphone HCl, oxytretracycline, oxytocin, disodium pamidronate, pancreptipase, pancuronium bromide, paromomycin sulfate, parozetin HCl, pencilamine, penicillins for general information, penicillin G, penicillin V, patassium, pentazocine, sodium pentobarbital, sodium polysulfate pentosan, pentoxifylline, pergolide mesylate, phenobarbital, phenoxybenzamine HCl, pheylbutazone, phenylephrine HCl, phenypropanolamine HCl, phenytoin sodium, pheromones, parenteral phosphate, phytonadione/vitamin K-1, pimobendan, piperazine, pirlimycin HCl, piroxicam, polysulfated glycosaminoglycan, ponazuril, potassium chloride, pralidoxime chloride, praziquantel, prazosin HCl, prednisolone/prednisone, primidone, procainamide HCl, procarbazine HCl, prochlorperazine, propantheline bromide, propofol, propranolol HCl, protamine sulfate, pseudoephedrine HCl, hydrophilic muc psyllium yloid, pyrantel pamoate, pyridostlgmine bromide, pyrylamine maleate, pyrimethamine, quinacrine HCl, quinidine, ranthidine HCl, rifampin, s-adenosyl-methionine (SAMe), saline/hyperosmotic laxative, selamectin, selegiline HCl, deprenyl, sertraline HCl, sevelamer HCl, sevoflurane, silymarin/milky title, sodium bicarbonate, sodium polystyrene sulfonate, sodium stibogluconate, sodium sulfate, sodium thiosulfate, somatotropin, sotalol HCl, spectinomycin HCl, spironolactone, stanozolol, streptokinase, streptozocin, succimer, succinylcholine chloride , sucralfate, sufentanil citrate, sulfachlorpyridazine sodium, sulfadiazine/trimetroprim, sulfamethoxazole/trimethoprim, sulfadimentoxine, sulfadimethoxine/ormethoprim, sulfasalazine, taurine, tepoxaline, terbinafline HCl, terbutaline sulfate, testosterone, tetracycline HCl, thiabendazole, sodium thiacetarsamide, thiamine HCl, thioguanine, sodium thiopental, thyrotropin, tiamulin, ticarcillin disodium, tiletamine HCl, z olazepam HCl, tilmocsin, thiopronin, tobramycin sulfate, tocainide HCl, tolazoline HCl, telfenamic acid, topiramate, tramadol HCl, trimcinolone acetonide, trientine HCl, trilostane, trimepraxin tartrate w/prednisolone, tripelennamine HCl, tylosin, urdosiol, valproic acid, vanadium , vancomycin HCl, vasopressin, vecuronium bromide, verapamil HCl, vinblastine sulfate, vincristine sulfate, vitamin E/selenium, warfarin sodium, xylazine HCl, yohimbine HCl, zidovudine (AZT), zinc zinzo acetate/zinc sulfate, zonisamide and their mixtures.

[0001] In one embodiment of the invention, pyrazole compounds such as phenylpyrazoles as described above (e.g. fipronil) are known in the art and are suitable active alone or in combination with other active compounds of the present invention. Examples of such pyrazole compounds include, but are not limited to, those described in US Patent Nos. 6,001,384; 6,010,710; 6,083,519; 6,096,329; 6,174,540; 6,685,954 6,998,131; 7,759,381 and 8,445,519 each assigned to Merial, Ltd., (Duluth, GA, USA) and incorporated herein by reference.

[0002]-5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-(trifluoromethylsulfinyl)-1H-pyrazol-3-carbonitrile (i.e. fipronil), 1H-pyrazol-3 -carbonitrile, 1-[2,6-dichloro-4-trifluoromethyl)phenyl]-5-methyl-4-[(trifluoromethyl)sulfinyl] (i.e. ML465) and 1-(2-chloro-6-fluoro-4 -trifluoromethylphenyl)-4-dichlorofluoro-methylsulfinyl-5-methylpyrazole-3-carbonitril (i.e. ML198) are specifically referenced.

[0003] In another embodiment of the invention, nodulisporic acid and its derivatives (a class of known acaricide, anthelmintic agents, antiparasitic and insecticides) can be added to the compositions of the invention. These compounds are used to treat or prevent infections in humans and animals and are described, for example, in US Patent Nos. 5,399,582 and 5,962,499. The composition may include one or more of the nodulisporic acid derivatives known in the art, including all stereoisomers, such as those described in the above-cited literature.

[0004] In another embodiment of the invention, one or more macrocyclic lactones, which act as an acaricide, an anthelmintic agent and insecticide can be added to the compositions of the invention. Macrolides are well known in the art. See, for example, Macrolides - Chemistry, pharmacology and clinical uses - edited by Bryskier et al., published by Amette Blackwell, (1993). Macrolides include, but are not limited to, 12-membered ring macrolides (eg, methimycin, neomethimycin, CA-17, littorin); 14-membered ring macrolides (e.g. erythromycin AF, oleandomycin, sporeamycin, roxithromycin, dirithromycin, flurithromycin, clarithromycin, davercin); 15-membered ring macrolides (eg, azithromycin); 16-ring-membered macrolides (eg, josamycin, cytasamycin, spiramycin, midecamycin, rocitamycin, myocamycin) and 17-ring-membered macrolides (eg, lancadicin).

[0005] Macrocyclic lactones also include, but are not limited to, avermectins such as abamectin, dimadectin, doramectin, emamectin, eprinomectin, ivermectin, latidectin, lepimectin, selamectin and milbemycins such as milbemectin, milbemycin D, moxidectin and nemadectin. Also included are 5-oxo and 5-oxime derivatives of said avermectins and milbemycins.

[0006] Examples of combinations of arylpyrazole compounds with macrocyclic lactones include, but are not limited to, those described in US Patent Nos. 6,426,333; 6,482,425; 6,962,713 and 6,998,131 - each assigned to Merial, Ltd. (Duluth, GA, USA).

[0007] The macrocyclic lactone compounds are known in the state of the art and can be easily obtained commercially or through synthetic techniques known in the state of the art. Reference is made to widely available technical and commercial literature. For avermectins, ivermectin and abamectin, reference can be made, for example, to the work "Ivermectin and Abamectin", 1989, by M.H. Fischer and H. Mrazik, William C. Campbell, published by Springer Verlag., or Albers-Schonberg et al. (1981), “Avermectins Structure Determination”, J. Am. Chem. Soc., 103, 4216-4221. For doramectin, "Veterinary Parasitology", vol. 49, No.1, July 1993, 5-15 may be consulted. For milbemycins, reference may be made, inter alia, to Davies H.G. et al., 1986, "Avermectins and Milbemycins", Nat. Product Rep., 3, 87-121, Mrozik H. et al., 1983, Synthesis of Milbemycins from Avermectins, Tetrahedron Lett., 24, 5333-5336, US patent 4,134,973 and EP 0,677,054.

[0008] Macrocyclic lactones are natural products or are semi-synthetic derivatives thereof. The structure of avermectins and milbemycins are closely related, for example, through the sharing of a 16-membered macrocyclic lactone ring complex; milbemycins lack the glycosidic portion of avermectins. Avermectins are natural products described in US Patent No. 4,310,519 to Albers-Schonberg et al, and 22,23-dihydro avermectin compounds are disclosed in Chabala et al, US Patent No. 4,199,569. See further from Kitano, US Patent No. 4,468,390, Beuvry et al, US Patent No. 5824653, EP 0 007 812 A1, UK Patent Specification 1 390 336, EP 0 002 916, and Ancare New Zealand Patent No. No. 237,086, inter alia naturally occurring milbemycins are described in Aoki et al., US Patent No. 3,950,360, as well as in the various references cited in "The Merck Index", 12th Ed., S. Budavari, Ed., Merck & Co., Inc. Whitehouse Station, New Jersey (1996). Latidectin is described in the section "International Common Names for Pharmaceutical Substances (INN)," WHO Medicines Information, vol. 17, no. 4, pp. 263-286, (2003). Semi-synthetic derivatives of these classes of compounds are well known in the art and are described, for example, in US Patent No. 5,077,308, US Patent No. 4,859,657, US Patent No. 4,963,582, US Patent No. 4,855,317, US Patent No. No. 4,871,719, US Patent No. 4,874,749, US Patent No. 4,427,663, US Patent No. 4,310,519, US Patent No. 4,199,569, US Patent No. 5,055,596, US Patent No. 4,973,711, US Patent No. 4,978,677, US Patent No. 4,920,148 and EP 0 667 054.

[0009] In another embodiment of the invention, the class of acaricides or insecticides known as insect growth regulators (IGR) can also be added to the compositions of the invention.

[00010] Compounds belonging to this group are well known to the skilled artisan and represent a wide range of different chemical classes. All these compounds act by interfering with the development or growth of insect pests. Insect growth regulators are described, for example, in US Patent No. 3,748,356; US Patent No. 3,818,047; US Patent No. 4,225,598; US Patent No. 4,798,837; US Patent No. 4,751,225, EP 0179022 or UK 2,140,010, as well as US Patent No. s. 6,096,329 and 6,685,954 (both assigned to Merial Ltd., Duluth, GA). Examples of suitable IGRs for use include, but are not limited to, methoprene, pyriproxyfen, hydroprene, cyromazine, fluazuron, lufenuron, novaluron, pyrethroids, formamidines and 1-(2,6-difluorobenzoyl)-3-(2-fluoro-4- (trifluoromethyl)phenylurea an anthelmintic agent that can be combined with the compound of the present invention to form a composition that can be a benzene disulfonamide compound, which includes but is not limited to clorsulon or a cestodal agent, which includes but is not limited to praziquantel, pyrantel or morantel.

[00011] An antiparasitic agent that can be combined with the compound of the present invention to form a composition can be a biologically active peptide or a protein including, but not limited to, depsipeptides, which act at the neuromuscular junction by stimulating pre- synapses belonging to the secretin receptor family resulting in paralysis and death of the parasites. In one embodiment of depsipeptides, the depsipeptide is emodepsid.

[00012] An insecticidal agent that can be combined with the compound of the invention to form a composition can be a spinosyn (e.g. spinosad) or a substituted pyridylmethyl compound such as imidacloprid. Agents of this class are described above and, for example, in US Patent No. 4,742,060 or EP Patent 0,892,060. It would be well within the skill level to decide which individual compound can be used in the inventive formulation to treat an infestation. particular to an insect.

[00013] Insect repellants, alone or in combination with the above, can also be considered active in the present invention. Examples include pyrethroids such as allethrin, alphamethrin, bioresmethrin, bifenthrin, cycloprothrin, cyflutyrin, decamethrin, cyhalothrin, cypermethrin, deJtamethrin, alpha-cyano-3-phenyl-2-methylbenzyl 2,2-dimethyl-3-(2-chloro- 2 trifluoromethylvinyl)cyclopropanecarboxylate, fenpropathrin, fenfluthrin, fenvalerate, flucitrinate, flumethrin, fluvalinate, permethrin, resmethrin and tralomethrin.

[00014] In general, the repellent agent or pesticide is included in a dose of between about 0.1 μg and about 10 mg. In one embodiment of the invention, the repellent or pesticide agent is included in a dose of between about 1 µg and about 10 mg. In another embodiment of the invention, the repellent or pesticide agent is included in a dose of from about 5 to about 200 µg/kg of animal weight. In yet another embodiment of the invention, the repellent or pesticide agent is included in a dose of between about 0.1 to about 10 mg/kg of animal weight. In yet another embodiment of the invention, the repellent or pesticide agent is included at a dose of between about 0.5 to 50 mg/kg.

[00015] The weight ratios of the 1-aryl-5-alkyl pyrazole compound and any additional pesticidal agent are, for example, between about 5/1 and about 10,000/1. However, one skilled in the art will be able to select the appropriate ratio of the 1-aryl-5-alkyl pyrazole compound and the additional pesticidal agent for the intended host and use thereof.

[00016] In another embodiment of the invention, the formulation may be in the form of a ready-to-use solution as described in US Patent No. 6,395,765, incorporated herein by reference. In addition to the active compound(s), the solution may contain a crystallization inhibitor. The crystallization inhibitor may be present in a proportion of about 1 to about 20% (w/v). Alternatively, the crystallization inhibitor may be present in a proportion of from about 5 to about 15%. In another embodiment the amount of crystallization inhibitor, the value corresponds to the test in which 0.3 ml of a solution comprising 10% (w/v) of the 1-aryl-5-alkyl pyrazole compound in the liquid vehicle and 10% of the inhibitor are deposited on a glass slide at 20 °C and allowed to stand for 24 hours. The blade is then observed with the naked eye. Acceptable inhibitors are those whose addition predicts few (eg, less than ten crystals) or no crystals.

[00017] Crystallization inhibitors that are useful for the invention include, but are not limited to: (a) polyvinylpyrrolidone, polyvinyl alcohols, copolymers of vinyl acetate and vinylpyrrolidone, polyethylene glycols, benzyl alcohol, mannitol, glycerol, sorbitol or polyoxyethylene sorbitan esters; lecithin or sodium carboxymethyl cellulose; or acrylic derivatives such as methacrylates; (b) anionic surfactants such as alkaline stearates (e.g. sodium, potassium or ammonium stearate); calcium stearate or triethanolamine stearate; sodium abietate; alkyl sulfates, which include, but are not limited to, sodium lauryl sulfate and sodium acetyl sulfate; sodium dodecylbenzenesulfonate or sodium dioctylsulfosuccinate; or fatty acids (eg coconut oil); (c) cationic surfactants, such as water-soluble quaternary ammonium salts of the formula N+R'R"R"'R""Y-, wherein the radicals R are identical or different optionally hydroxylated hydrocarbon radicals, and Y is a anion of a strong acid, such as halide, sulfate and sulfonate anions; cetyltrimethylammonium bromide is one of the cationic surfactants that can be used; (d) amine salts of the formula N + R'R "R"', wherein the radicals R are identical or different, optionally hydroxylated hydrocarbon radicals; octadecylamine hydrochloride is one of the cationic surfactants that can be used; (e) nonionic surfactants, such as polyoxyethylene sorbitan esters, optionally, for example, Polysorbate 80, or polyoxyethylene alkyl ethers; polyethylene glycol stearate, polyoxyethylene derivatives of castor oil, polyglycerol esters, polyoxyethylene fatty alcohols, polyoxyethylene fatty acids or copolymers of ethylene oxide and propylene oxide; (f) amphoteric surfactants, such as betaine substituted lauryl compounds; or (g) a mixture of at least two of the compounds listed in (a) - (f) above.

[00018] In another embodiment of the invention, the formulation may also comprise an antioxidant agent intended to inhibit oxidation in air. This agent may be present in a proportion from about 0.005 to about 1% (w/v). Alternatively, the anti-oxidant agent may be present in a proportion of from about 0.01 to about 0.05%. Anti-oxidant agents include, but are not limited to, butylated hydroxyanisole, butylated hydroxytoluene, ascorbic acid, sodium metabisulfite, propyl gallate, sodium thiosulfate, or a mixture of no more than two of the above.

[00019] Embodiments of the invention may also include colorants, flavors and pH stabilizers known in the state of the art. Examples of dyes include, but are not limited to, titanium dioxide and iron oxide. A comprehensive list of acceptable dyes can be found in 37 CFR, Title 21, Part 74. Dyes and pH stabilizers are conventional and known in the art.

[00020] The invention is also directed to a method of treating an animal (e.g. a mammal) against ectoparasite infection by administering an ectoparasiticidally effective amount of the composition of the invention. Mammals that may be treated include, but are not limited to, humans, cats, dogs, cattle, chickens, cows, deer, goats, horses, llamas, pigs, sheep, and yaks. In one embodiment of the invention, the treated mammals are humans, cats or dogs.

[00021] In another embodiment for treating ectoparasites, the ectoparasite is one or more of an insect or arachnid, including those of the genera Ctenocephalides, Rhipicephalus, Dermacentor, Ixodes, Boophilus, Ambylomma, Haemaphysalis, Hyalomma, Sarcoptes, Psoroptes, Otodectes, Chorioptes, Hypoderma. Damalinia, Linognathus, Haematopinus, Solenoptes, Trichodectes and Felicola.

[00022] In another embodiment for treatment against ectoparasites, the ectoparasite is from the genera Ctenocephalides, Rhipicephalus, Dermacentor, Ixodes and/or Boophilus. Treated ectoparasites include, but are not limited to, fleas, ticks, mites, mosquitoes, flies, lice, blowflies and combinations thereof. Specific examples include, but are not limited to, cat and dog fleas (Ctenocephalides felis, Ctenocephalides sp. and the like), ticks (Rhipicephalus sp., Ixodes sp., Dermacentor sp., Amblyoma sp. and the like), and the mites (Demodex sp., Sarcoptes sp., Otodectes sp. and the like), lice (Trichodectes sp., Cheyletiella sp., Lignonathus sp., and the like), mosquitoes (Aedes sp., Culex sp., Anopheles sp., and a like) and flies (Hematobia sp., Musca sp., Stomoxys sp., Dematobia sp., Cochliomyia sp., and the like). In yet another embodiment for treating ectoparasites, the ectoparasite is a flea and/or tick.

[00023] Additional examples of ectoparasites include, but are not limited to, the tick genus Boophilus, especially those of the microplus (tick), decoloratus and annulatus species; myiasis, such as Dermatobia hominis (known as Berne in Brazil) and Cochliomyia hominivorax (greenbottle); Sheep myiasis such as Lucilia sericata, Lucilia cuprina (known as serious blowfly in Australia, New Zealand and South Africa). Suitable flies, ie those whose adult constitute the parasite, such as Haematobia irritans (horn fly): lice, such as Linognathus vitulorum, etc.; and mites such as Sarcoptes scabici and Psoroptes ovis. The above list is not exhaustive and other ectoparasites are well known in the art which are harmful to humans and animals. These include, for example, migratory dipteran larvae.

[00024] When an anthelmintic agent is added to the composition of the present invention, the composition can also be used to treat against endoparasites, such as those helminths selected from the group consisting of Anaplocephala, Ancylostoma, Anecator, Ascaris, Capillaria, Cooperia, Dipylidium, Dirofilaria, Echinococcus, Enterobius, Fasciola, Haemonchus, Oesophagostumum, Osteriagia, Toxocara, Strongy Leathers, Toxascaris, Trichinella, Trichuris and Trichostrongylus.

[00025] In another embodiment, compounds of the invention are administered in spot-on formulations. While not wishing to be bound by theory, these formulations are believed to work by gradual diffusion of the encapsulated active(s) into the polymer or polymer mixture that adheres to hair and skin after evaporation of the solvent(s), and dissolution of the dose. in the natural oils of the skin or skin of the host. Thus, the polymer becomes a reservoir that inhabits and protects active(s) from environmental stresses such as rain, duration of treatment period and active(s) continues to progressively diffuse from the polymer and replenish therapeutic amounts. of active(s) washed away during rain or removed by other means (e.g. licking, rubbing).

[00026] From there, the active agent(s) distributes itself around the host's body via the sebaceous glands of the skin. The therapeutic agent may also remain in the sebaceous glands.

[00027] In an administration site embodiment, a single formulation that contains the active agent in a substantially liquid carrier and in a form that makes a single application possible, (e.g., as a pour-on or may be applied as a spot-on to one or more sites on the animal's body) will be administered to the animal along a localized region of the animal, for example between the two shoulders or along the spine. The invention is further described by the following non-limiting examples which further illustrate the invention, and are not intended and should not be construed to limit the scope of the invention.

[00028] In one application of the invention, Haematobia irritans (L., i.e., horn fly), is a livestock pest that causes significant economic losses estimated at over $1 billion in the United States annually. Horn fly infestation leads to decreased milk production, decreased calf weaning weights, and decreased weight gain in growing cattle. (Domingues, L.N., et al., Discovery of the Rdl mutation in association with a cyclodiene resistant population of horn flies, Haematobia irritans (Diptera: Musidae). Vet. Parasitol. (2013)).

[00029] Current commercially available topical solutions to control the horn fly population in cows provide limited duration of protection lasting from several days to about two weeks. Current treatments require more frequent re-application due to a wash-off after exposure to environmental conditions such as rain. Extension of effectiveness of a month or more will provide ongoing protection against horn fly with less frequent applications. Fewer applications will be less stressful for the animals and less time and labor consumption for the farmers. This can be achieved by using active ingredients of superior efficacy, using an improved delivery mechanism, or both.

[00030] Although many different active agents can work with the formulation of the invention, 1H-pyrazol-3-carbonitrile, 1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-5-methyl-4-[( trifluoromethyl)sulfinyl] (ie ML465) is the compound used to test topical formulations for horn fly control in cows over a period of one month or longer.

water resistance

[00031] In-vivo and in-vitro studies were performed to compare the water resistance of formulations prepared with lipophilic solvents and with polymers. The results indicate that an outlet washout strength is higher for polymer formulations. The water resistance of known solvent systems used clinically in in vivo studies A and B was evaluated and the results are summarized in Table 1A. Table 1 below shows the water resistance of conventional pour-on formulations used in clinical studies A and B. Table 1.

[00032] Trials A and B with traditional formulations containing ML465 did not result in a desired duration of efficacy due to the impact of water exposure during rains that occur randomly and have highly variable intensity. It can be seen that the amount of ML465 is washed out at or below 10% of the applied dose, which indicates a marked decrease after exposure to water. This was not enough to support thirty days of lasting effectiveness. Thus, effectiveness may depend on the resistance of the solvent system to exposure to water.

[00033] The in vivo studies in Table 1 were followed up with the in vitro studies performed to assess the water resistance of "conventional" solvent systems. The conventional pour-on solvent formulations described below were tested using ML465 as the active under water exposure for 20 and 40 minutes. Table 2.

[00034] Laboratory data indicate that ML465 is washed off after repeated exposure to water for all formulations tested. This means that with each precipitation, of random duration and intensity, the concentration of ML465 on the skin will gradually decrease.

[00035] Next, the water resistance of the solvent systems of the invention was tested in vitro. Table 3 shows the percentage of active ML465 lost after exposure to water for 40 minutes. The formulation of the invention reduced (i.e. improved) the percentage of ML465 removed after exposure to water compared to conventional solvent systems in Tables 1 and 2. Table 3.

[00036] The entrapment of an active in the polymer and continuous diffusion of an active out of the polymer will ensure protection against environmental conditions such as rain, and continuous replenishment and the presence of an active in the skin to provide a treatment for the skin. duration of the desired treatment period. The lipids present in the animals' skin will act as a vehicle and will also be continuously replenished by the animal.

[00037] The rate of diffusion can be controlled through the composition of the polymer part of the formulation, such as the use of a single polymer, mixtures of multiple polymers or polymers of various molecular weights. Furthermore, the rate of diffusion can also be controlled by adding a plasticizer, in different compositions and amounts. The plasticizer can be an external agent or the sebacious lipids naturally present in the skin.

[00038] This formulation for topical administration of a pharmaceutical active ingredient is through the application of a liquid formulation with a solvent system consisting of a single volatile solvent or a combination of volatile solvents, a polymer or a combination of polymers, one or more active substances, and, optionally, a plasticizer or a combination of plasticizers. Examples of tested solvent systems are shown below. It should be possible for a skilled person to create additional examples that expand the classes of materials that may be used. Solvents contemplated by the present invention include a saturated aliphatic ketone (e.g., methyl isobutyl ketone) or an ester (e.g., butyl acetate or ethyl lactate). These solvents can further be combined with, for example, isopropyl alcohol or ethanol. Polymers contemplated by the present invention include at least one water-insoluble polymer (e.g., a polyvinyl acetate of different molecular weights), which can be combined with water-soluble polymers (e.g., povidones, polyvinyl alcohol, or cellulose acetate).

[00039] Optionally, the formulation of the present invention may include an external aliphatic ester plasticizer (e.g., acetyl tributyl citrate), perfumes, and coloring agents.

[00040] It should be noted that isopropanol may be a solvent or a plasticizer. Neither polymer nor ML465 dissolves in isopropanol. It was added initially to reduce the strong odor of isobutyl methyl ketone. Surprisingly, it was observed that the addition of isopropanol impacted the release rate of ML465 from the matrix, thus making isopropanol a plasticizer in this case. For other active agents they may be either miscible with or dissolve in isopropanol which may be a solvent.

[00041] After administration, the liquid formulation does not have to spread out to cover an animal's body like a conventional topical formulation. A volatile solvent(s) evaporates more quickly, leaving a polymer matrix dressing that cannot be evenly distributed around an application site. The polymer will adhere to the hair or skin which carries an active that is retained in the polymer. The therapeutic effect is achieved by diffusing the active compound(s) out of the polymer and mixing it with the lipids present in an animal's skin which will transport it to cover the animal's body. The degree of diffusion of the formulation can be controlled, through the selection of solvents and spreading agents.

[00042] Surprisingly, the addition of isopropanol to the methyl isobutyl ketone during solution preparation resulted in an equal or even greater rate of diffusion of API out of the API/polymer mixture relative to the API/polymer mixture with the addition of a plasticizer. Isopropanol is not considered to be a traditional plasticizer for the polymer. It is postulated that their effect may be on the physical structure of the polymer film (such as creating additional porosity). The isopropanol concentration can be less than, equal to or greater than the polymer concentration, with the upper limit being a polymer/polymer combination solubility in a solvent system. Polyvinyl acetate does not dissolve in isopropanol, therefore isopropanol cannot completely replace methyl isobutyl ketone as there must be a sufficient amount of methyl isobutyl ketone for the polymer to dissolve.

[00043] This approach can be used to topically deliver various active agents to farm animals such as cows, sheep, pigs, horses or companion animals such as dogs and cats, and others, to protect against external parasites (e.g. , fleas, ticks, mites, flies, etc.) or internal parasites.

[00044] Various embodiments of the invention are given in the following examples.

[00045] Process: add methyl isobutyl ketone, in the amount of about 40% of the weight to be prepared into the container that can be hermetically closed, during the preparation of the formulation; add polymer and mix until dissolved, about 2 - 3 hours; add ML465, mix until dissolved; 100% QS with methyl isobutyl ketone, mix. Make sure the container is tightly closed to prevent solvent evaporation. Example 2

[00046] Process: add methyl isobutyl ketone, in the amount of about 40% of the weight to be prepared into the container that can be hermetically closed during the preparation of the formulation; add polymers and mix until dissolved, about 2 - 3 hours; add ML465, mix until dissolved; 100% QS with methyl isobutyl ketone, mix. Make sure the container is tightly closed to prevent solvent evaporation. Example 3

[00047] Process: add methyl isobutyl ketone, in the amount of about 40% of the weight to be prepared, into the container that can be hermetically closed, during the preparation of the formulation; add polymer and mix until dissolved, about 2 - 3 hours; add ML465, mix until dissolved; slowly add isopropanol flakes while it will be formed, continue to mix until dissolved and the flakes in the solution are clear, you can add remaining isopropyl methyl ketone and mix until the solution is clear. Make sure the container is tightly closed to prevent solvent evaporation.

[00048] Process: add methyl isobutyl ketone, in the amount of about 55% of the weight to be prepared, into the container that can be hermetically closed during the preparation of the formulation; add polymer and mix until dissolved, about 2 - 3 hours; add ML465, mix until dissolved; 100% QS with methyl isobutyl ketone, mix. Make sure the container is tightly closed to prevent solvent evaporation.

[00049] Process: add methyl isobutyl ketone, in the amount of about 55% of the weight to be prepared, into the container that can be hermetically closed during the preparation of the formulation; add polymer and mix until dissolved, about 2 - 3 hours; add ML465, mix until dissolved; Slowly add isopropanol flakes, while it is formed, continue mixing until dissolved and the flaked solution is clear, you can add the rest of the methyl isopropyl ketone at the same time as the isopropanol and mix until the solution is clear. Make sure the container is tightly closed to prevent solvent evaporation. Example 6

[00050] Process: add methyl isobutyl ketone in the amount of about 55% by weight to be prepared into the hermetically sealed container during preparation of the formulation; add the polymer and mix until dissolved, about 2 - 3 hours; add ML465, mix until dissolved; adding acetyl tributyl citrate; slowly add isopropanol - whilte flakes will be formed, the remainder of the isopropyl methyl ketone can be added at the same time as the isopropanol addition, continue to mix until the flakes are dissolved and the solution is clear, you can add the remainder of the ketone isopropyl methyl at the time of mixing and mixing until the solution is clear. Make sure the container is tightly closed to prevent solvent evaporation. Example 7 Ingredients Function % W/W ML465 Active 4.0 Polyvinyl Acetate MW 100000 Polymer 20.0 Isopropanol Additive 25 Methyl Isobutyl Ketone Solvent QS 100%

[00051] Process: add methyl isobutyl ketone, in the amount of about 50% of the weight to be prepared, into the container that can be hermetically closed, during the preparation of the formulation; add polymer and mix until dissolved, about 2-3 hours; add ML465, mix until dissolved; Add isopropanol flakes slowly while it is being formed, continue to mix until dissolved and the flaked solution is clear, the remainder of the isopropyl methyl ketone can be added at the same time as the addition of isopropanol, and mix until the solution is dissolved. be clear. Make sure the container is tightly closed to prevent solvent evaporation.

[00052] Process: add methyl isobutyl ketone, in the amount of about 50% of the weight to be prepared into the container that can be hermetically closed, during the preparation of the formulation; add polymer and mix until dissolved, about 2 - 3 hours; add ML465, mix until dissolved; add acetyl tributyl citrate and the remainder of the methyl isopropyl ketone and mix. Make sure the container is tightly closed to prevent solvent evaporation. Example 9

[00053] Process: add methyl isobutyl ketone, in the amount of about 65% of the weight to be prepared, into the container that can be hermetically closed, during the preparation of the formulation; add polymer and mix until dissolved, about 2-3 hours; add permethrin and mix; 100% QS with methyl isobutyl ketone, mix. Make sure the container is tightly closed to prevent solvent evaporation. Example 10

[00054] Process: add methyl isobutyl ketone, in the amount of about 50% of the weight to be prepared into the container that can be hermetically closed, during the preparation of the formulation; add polymer and mix until dissolved, about 2 - 3 hours; add permethrin, mix; Slowly add isopropanol - white flakes will be formed, continue mixing until dissolved and flakes solution is clear, the remainder of the isopropyl methyl ketone can be added at the same time as adding isopropanol, and mix until the solution is clear. Make sure the container is tightly closed to prevent solvent evaporation. Example 11

[00055] Process: add methyl isobutyl ketone, in the amount of about 50% of the weight to be prepared, into the container that can be hermetically closed, during the preparation of the formulation; add polymer and mix until dissolved, about 2-3 hours; add permethrin, mix; slowly add isopropanol - white flakes will be formed, continue mixing until dissolved and flakes solution is clear, the remaining isopropyl methyl ketone can be added at the same time as adding isopropanol, and mix until the solution is clear. Make sure the container is tightly closed to prevent solvent evaporation.

[00056] Process: add methyl isobutyl ketone, in the amount of about 50% of the weight to be prepared, into the hermetically sealed container, during the preparation of the formulation; add polymer and mix until dissolved, about 2 - 3 hours; add permethrin, mix; add tributyl acetyl citrate and the remainder isopropyl methyl ketone and mix. Make sure the container is tightly closed to prevent solvent evaporation.

[00057] Process: add methyl isobutyl ketone, in the amount of about 50% of the weight to be prepared, into the container that can be hermetically closed, during the preparation of the formulation; add polymer and mix until dissolved, about 2 - 3 hours; add permethrin, mix; add tributyl acetyl citrate and the remainder of the isopropyl methyl ketone and mix. Make sure the container is tightly closed to prevent solvent evaporation. Example 14 [not prepared with active, but prepared without active]

[00058] Process: add methyl isobutyl ketone, in the amount of about 50% of the weight to be prepared, into the container that can be hermetically closed, during the preparation of the formulation; add polymer and mix until dissolved, about 2 - 3 hours; add ML465, mix until dissolved; add the remainder of the methyl isopropyl ketone and mix. Make sure the container is tightly closed to prevent solvent evaporation.

[00059] Process: add methyl isobutyl ketone, in the amount of about 50% of the weight to be prepared, into the container that can be hermetically closed, during the preparation of the formulation; add polymer and mix until dissolved, about 2-3 hours; add ML465, mix until dissolved; add acetyl tributyl citrate and the remainder isopropyl methyl ketone and mix. Make sure the container is tightly closed to prevent solvent evaporation. Example 16 (not prepared exactly with PVAc MW 50000, but prepared with MW 100000)

[00060] Process: add methyl isobutyl ketone, in the amount of about 50% of the weight to be prepared into the container that can be hermetically closed, during the preparation of the formulation; add polymer and mix until dissolved, about 2 - 3 hours; add ML465, mix until dissolved; add tributyl acetyl citrate and the remaining isopropyl methyl ketone and mix. Make sure the container is tightly closed to prevent solvent evaporation.

[00061] Process: add methyl isobutyl ketone, in the amount of about 50% of the weight to be prepared into the container that can be hermetically closed, during the preparation of the formulation; add polymer and mix until dissolved, about 2 - 3 hours; add ML465, mix until dissolved; slowly add isopropanol flakes while it will be formed, continue mixing until dissolved and the flaked solution is clear, the rest of the isopropyl methyl ketone can be added at the same time as the addition of isopropanol, mix until the solution is clear. Make sure the container is tightly closed to prevent solvent evaporation.

[00062] Process: add methyl isobutyl ketone, in the amount of about 50% of the weight to be prepared, into the container that can be hermetically closed, during the preparation of the formulation; add polymers and mix until dissolved, about 2 - 3 hours; add ML465, mix until dissolved; slowly add isopropanol flakes while it will be formed, continue mixing until dissolved and the flaked solution is clear, the rest of the isopropyl methyl ketone can be added at the same time as the addition of isopropanol, mix until the solution is clear. Make sure the container is tightly closed to prevent solvent evaporation. Example 19

[00063] Process: add methyl isobutyl ketone, in the amount of about 50% of the weight to be prepared, into the container that can be hermetically closed, during the preparation of the formulation; add MW 100,000 polyvinyl acetate and mix until dissolved, about 2-3 hours; add ML465, mix until dissolved; slowly add isopropanol - white flakes will be formed, continue to mix until dissolved and the flake solution is clear; add Kollidon SR and mix until dissolved; the remaining isopropyl methyl ketone can be added at the same time as the addition of Kollidon SR, mixing until the solution is clear. Make sure the container is tightly closed to prevent solvent evaporation. Example 20 - Film made from this crystallized solution

[00064] Process: add methyl isobutyl ketone, in the amount of about 50% of the weight to be prepared into the container that can be hermetically closed, during the preparation of the formulation; add polymer and mix until dissolved, about 2 - 3 hours; add ML465, mix until dissolved; adding acetyl tributyl citrate and mixing; slowly add isopropanol - white flakes will be formed, continue to mix until dissolved and flakes solution is clear; the remaining isopropyl methyl ketone can be added at the same time as the isopropanol addition. Make sure the container is tightly closed to prevent solvent evaporation. Example 21 - Film made from this crystallized solution

[00065] Process: add methyl isobutyl ketone, in the amount of about 50% of the weight to be prepared into the container that can be hermetically closed, during the preparation of the formulation; add polymer and mix until dissolved, about 2 - 3 hours; add ML465, mix until dissolved; adding acetyl tributyl citrate and mixing; slowly add isopropanol - white flakes will be formed, continue to mix until dissolved and flakes solution is clear; the remainder of the isopropyl methyl ketone can be added at the same time as the isopropanol addition. Make sure the container is tightly closed to prevent solvent evaporation.

Claims (16)

1. A formulation for topical administration in the form of a solution characterized in that it comprises: at least one veterinary active ingredient having ectoparasiticide activity, wherein said veterinary active ingredient comprises an arylpyrazole compound; a volatile solvent system containing at least one dissolved polymer; wherein said volatile solvent system consists of one or more solvent(s) selected from the group consisting of methyl isobutyl ketone, butyl acetate and ethyl lactate and wherein the volatile solvent represents from 50 to 94% w/w of the composition; wherein said polymer comprises a water-insoluble polymer which is polyvinyl acetate, alone or in combination with a water-soluble polymer; and optionally, a plasticizer; wherein, after dosing, evaporation of the volatile solvent provides a water-resistant polymer matrix in which the active ingredient is trapped. 2. Formulation according to claim 1, characterized in that the solvent is methyl isobutyl ketone. 3. Formulation according to claim 1, characterized in that the solvent is butyl acetate. 4. Formulation according to claim 1, characterized in that the solvent is ethyl lactate. 5. Formulation according to claim 1, characterized in that the polyvinyl acetate is MW 100,000 polyvinyl acetate. 6. Formulation according to claim 7, characterized in that the polyvinyl acetate is MW 50,000 polyvinyl acetate. 7. Formulation according to claim 1, characterized in that the water-soluble polymer is a povidone. 8. Formulation according to claim 1, characterized in that the water-soluble polymer is polyvinyl alcohol. 9. Formulation according to claim 1, characterized in that the water-soluble polymer is ethylcellulose. 10. Formulation according to claim 1, characterized in that the optional plasticizer is an aliphatic ester. 11. Formulation according to claim 10, characterized in that the aliphatic ester is acetyl tributyl citrate. 12. Formulation according to claim 1, characterized in that the water-insoluble polymer is from 5% to 40% w/w of the composition. 13. Formulation according to claim 1, characterized in that the water-soluble polymer is from 5% to 40% w/w of the composition. 14. Formulation, according to claim 1, characterized in that the plasticizer is from 0.5% to 5% w/w of the composition. 15. Formulation according to claim 1, characterized in that it also comprises isopropanol. 16. Use of a topical administration formulation as defined by claim 1, characterized in that it is for the manufacture of a drug for the therapeutic treatment and/or prophylactic treatment of an animal against an ectoparasite and/or an endoparasite.